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The Cohesin Complex in Mammalian Meiosis

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The Cohesin Complex in Mammalian Meiosis Received: 5 September 2018 | Revised: 29 October 2018 | Accepted: 29 October 2018 DOI: 10.1111/gtc.12652 REVIEW ARTICLE Genes to Cells The cohesin complex in mammalian meiosis Kei‐ichiro Ishiguro Institute of Molecular Embryology and Genetics, Kumamoto University, Abstract Kumamoto, Japan Cohesin is an evolutionary conserved multi‐protein complex that plays a pivotal role in chromosome dynamics. It plays a role both in sister chromatid cohesion and in es- Correspondence Kei‐ichiro Ishiguro, Institute of Molecular tablishing higher order chromosome architecture, in somatic and germ cells. Notably, Embryology and Genetics, Kumamoto the cohesin complex in meiosis differs from that in mitosis. In mammalian meiosis, University, Kumamoto, Japan. distinct types of cohesin complexes are produced by altering the combination of meio- Email: [email protected] sis‐specific subunits. The meiosis‐specific subunits endow the cohesin complex with Funding information Yamada Science Foundation; KAKENHI, specific functions for numerous meiosis‐associated chromosomal events, such as Grant/Award Number: #16H01257, chromosome axis formation, homologue association, meiotic recombination and cen- #16H01221, #17H03634 and #18K19304 tromeric cohesion for sister kinetochore geometry. This review mainly focuses on the Communicated by: Eisuke Nishida cohesin complex in mammalian meiosis, pointing out the differences in its roles from those in mitosis. Further, common and divergent aspects of the meiosis‐specific co- hesin complex between mammals and other organisms are discussed. 1 | OVERVIEW OF CHROMOSOME mechanism confers dominance on homologues for recombi- DYNAMICS DURING MEIOSIS nation to suppress sister chromatid exchange (SCE; Zickler & Kleckner, 1999). During these processes, the chromosomes The meiotic cell cycle consists of a single DNA replication undergo dynamic movement to facilitate homologue pairing followed by two rounds of chromosome segregation (meiosis and synapsis, which is driven by telomeres attached to the I and meiosis II), which halves the chromosome number to nuclear membrane (Hiraoka & Dernburg, 2009; Koszul & ultimately produce haploid gametes (Figure 1a). Remarkably, Kleckner, 2009; Shibuya & Watanabe, 2014). Consequently, the structure and behavior of the chromosomes during meio- those processes yield bivalent chromosomes, whereby two sis are markedly different to those in mitosis. During meiotic homologous chromosomes are physically connected by prophase I, sister chromatids are organized into protein- chiasmata. Chiasmata play an essential role in positioning aceous structures, termed axial element (AE) or chromosome homologous chromosomes so that they are captured by mi- axis, on which the synaptonemal complex (SC) is assembled crotubules from opposite poles during metaphase I (Sakuno, (Figure 1b; Zickler & Kleckner, 1999). Homologous chromo- Tanaka, Hauf, & Watanabe, 2011). At anaphase I, homolo- somes (homologues) then undergo pairing (Barzel & Kupiec, gous chromosomes are segregated toward opposite poles of 2008; Bhalla & Dernburg, 2008; Gerton & Hawley, 2005), the spindle by dissolution of chiasmata (Buonomo, Clyne, synapsis (Cahoon & Hawley, 2016; Page & Hawley, 2004) Fuchs, Loidl, & Uhlmann, 2000; Kudo, Wassmann, Anger, and meiotic recombination yielding crossovers, a process that Schuh, & Wirth, 2006). Thus, in contrast to mitosis, meio- produces physical linkages between homologues called chi- sis I homologous chromosomes rather than sister chromatids asmata (Figure 1b,c; Baudat, Imai, & Massy, 2013; Handel & are segregated into opposite directions to reduce the chro- Schimenti, 2010; Keeney, Lange, & Mohibullah, 2014; Lam mosome number by half (Watanabe, 2012). To accomplish & Keeney, 2015; Zickler & Kleckner, 2015). A crucial point this process in meiosis I, sister kinetochores face the same concerning meiotic recombination is that a specific active direction so that sister chromatids are co‐segregated into the This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2018 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd 6 | wileyonlinelibrary.com/journal/gtc Genes Cells. 2019;24:6–30. ISHIGURO Genes to Cells | 7 (a) Meiosis I Meiosis II Meta II Ana II Meiotic prophase I Meta IAna I Kinetochore Cohesin Chiasma Homolog (b) Transverse filament (c) SYCP1 Leptotene Zygotene Pachytene Diplotene Chromatin loops Synaptonemal complex (SC) Chiasma Homolog pairing/synapsis Axial element (AE) Meiotic recombination Telomere attachment to nuclear membrane Lateral elemnt (LE) Cohesin SYCP2 Central element (CE) SYCP3 FIGURE 1 Schematic of chromosome dynamics during meiosis. (a) Schematics of Meiosis I and Meiosis II. In meiosis I, homologous chromosomes, rather than sister chromatids, are segregated in opposite directions. At anaphase I, homologous chromosomes are segregated toward opposite poles of the spindle by the dissolution of chiasmata. In meiosis II, sister chromatids are segregated. (b) Cohesin plays crucial roles in meiosis‐specific chromosomal events during meiotic prophase I. Meiotic prophase I is prolonged compared to canonical G2 phase of cell cycle and is divided into five substages according to chromosome morphology. During meiotic prophase I, sister chromatids are organized into an axial element (AE). Cohesin loads onto chromatin during leptotene. Homologous chromosomes undergo pairing and synapsis through leptotene to zygotene. The synaptonemal complex (SC) is fully assembled between homologous chromosomes at pachytene. Meiotic recombination generates crossover between homologous chromosomes, yielding physical linkages called chiasmata. At diplotene, the SC is disassembled. Although cohesin largely dissociates from the chromosome arm after late pachytene, it persists around centromeres until metaphase II. (c) Schematic of the synaptonemal complex (SC). When the SC is assembled between homologous chromosomes, the AE is called lateral element (LE). Transverse filaments link two LEs. Cohesin locates at the most inner side of the LE same daughter cell, a process named monopolar kinetochore chromatid cohesion, which enables accurate chromosome orientation. In meiosis II, pairs of sister chromatids are seg- segregation in both mitosis and meiosis. In mammalian so- regated at anaphase II, which employs the same mechanisms matic cells, sister chromatid cohesion is mediated by cohesin, as mitosis. As described later, cohesin plays crucial roles in an evolutionary conserved multi‐protein complex. Cohesin all of these sequential chromosomal events during meiosis. contains four core subunits: two subunits of the structural maintenance of chromosomes (SMC) protein family, SMC1α and SMC3; the kleisin family protein RAD21/SCC1; and 2 | COHESIN COMPLEXES IN either one of two accessory subunits, SA1/STAG1 or SA2/ MITOSIS STAG2 (Figure 2a,c; Losada & Hirano, 2005; Nasmyth & Haering, 2009). Other accessory proteins, PDS5A/PDS5B When the chromosomes are replicated in the S‐phase, sister (Losada, Yokochi, & Hirano, 2005; Shintomi & Hirano, chromatids are held together by a mechanism called sister 2009), WAPL (Gandhi, Gillespie, & Hirano, 2006; Kueng, 8 | Genes to Cells ISHIGURO (a) (b) Mitotic cohesin Meiotic cohesin SMC1α SMC3 SMC1β SMC3 PDS5 WAPL PDS5 RAD21 SA1/SA2 REC8 SA3 RAD21L SORORIN RAD21 (c) Vertebrates Budding yeast Fission yeast Fly Nematoda SMC1α Smc1 Psm1 SMC1 SMC-1 SMC1β* SMC SMC3 Smc3 Psm3 SMC3 SMC-3 RAD21/SCC1 Scc1/Mcd1 Rad21 RAD21/Vtd COH-1 SCC-1/COH-2 Cohesin subunits αKleisin RAD21L* C(2)M* COH-3* COH-4* REC8* Rec8* Rec8* SOLO* REC-8* SA1 SA2 Scc3 Psc3 Stromalin/SA SCC-3 SA3* Rec11* SUNN* PDS5A PDS5B Pds5 Pds5 PDS5 PDS-5 WAPL Wpl1/Rad61 Wpl1 WAPL WAPL-1 SORORIN Dalmatian (* meiosis specific) (d) Proteolytic cleavage of kleisin subunit (e) Prophase pathway FIGURE 2 The cohesin complex in mitosis and meiosis. (a) Sister chromatids (indicated by blue bars) are held together by cohesin complexes in mitosis and meiosis. Cohesin contains four core subunits, SMC1α, SMC3, the kleisin family protein RAD21/SCC1 and SA1 or SA2. The cohesin complex in meiosis differs from that in mitosis. In mammalian germ cells, there are two meiosis‐specific kleisin subunits, REC8 and RAD21L. SMC1α and SA1/SA2 are substituted by the meiosis‐specific cohesin subunits, SMC1β and SA3, respectively. (b) PDS5A/PDS5B, WAPL and SORORIN are associated with the cohesin complex and regulate the dynamic interaction of cohesin with chromatin. SORORIN‐PDS5B interaction stabilizes cohesin loading onto the chromatin (lower). WAPL facilitates cohesin removal by competing with SORORIN for PDS5 binding (upper). (c) Mitotic and meiotic cohesin subunits are widely conserved throughout diverse species, as listed. (d) When sister chromatids are segregated, the kleisin subunit of the cohesin complex is cleaved by separase, dissolving sister chromatid cohesion. (e) In the prophase pathway, WAPL facilitates dissociation of cohesin by cleavage‐independent mechanism Hegemann, Peters, Lipp, & Schleiffer, 2006) and SORORIN (Figure 2b). Although SORORIN‐PDS5B interaction stabi- (Nishiyama, Ladurner, Schmitz, Kreidl, & Schleiffer, 2010; lizes cohesin loading onto the chromatin, WAPL facilitates Nishiyama, Sykora, Huis in ‘t Veld, Mechtler, & Peters, dissociation of cohesin
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